To understand Verastem's strategic pivot, one must first grasp just how intense the competition in the KRAS G12C arena has become.

Due to the lack of a distinct binding pocket, KRAS was once considered an "undruggable" target. It wasn't until 2021, when Amgen's KRAS G12C inhibitor Sotorasib received FDA approval, that this long-standing barrier was finally broken.

However, within just a few years, this pioneering target has become a fiercely contested "red ocean."

To date, five KRAS inhibitors have been approved globally, all targeting the G12C mutation. Of the approximately 70 KRAS research programs worldwide, over half focus on G12C.

Verastem's original strategy centered on "combination therapy for enhanced efficacy." The company aimed to combine its own RAF/MEK inhibitor avutometinib (which blocks the vertical RAF/MEK pathway) and FAK inhibitor defactinib (which inhibits the parallel FAK pathway) with Amgen's Sotorasib, forming dual or triple regimens to achieve deep suppression of the KRAS signaling network and overcome drug resistance.

Results from the RAMP 203 study showed that in the dual-therapy arm, among 30 treatment-naïve patients evaluable for efficacy, the objective response rate (ORR) was 40%, median progression-free survival (mPFS) was 11.1 months, and median follow-up time was 15.9 months.

For triple-therapy patients who were treatment-naïve, the median PFS could not be determined. Among triple-therapy patients who had previously received a G12C inhibitor, the median PFS was 3.6 months.

Yet, these seemingly "decent" results pale in comparison to the overwhelming advantages demonstrated by next-generation competitors.

Represented by Eli Lilly's Olomorasib, "second-generation" G12C inhibitors, when combined with pembrolizumab (Keytruda), achieved an impressive ORR of up to 71% in first-line treatment, with an ORR reaching 85% in patients with high PD-L1 expression.

Revolution Medicines' KRAS G12C (RAS-ON) inhibitor elironrasib reported an ORR of 42%, a disease control rate (DCR) of 79%, and an mPFS of 6.2 months in 24 previously treated patients with KRAS G12C-mutated non-small cell lung cancer.

On the other hand, the commercial performance of early-generation products has also fallen short of expectations.

Amgen's Sotorasib has seen annual sales plateau around $300 million since launch, while Bristol Myers Squibb's Adagrasib generated $126 million in revenue in 2024—a far cry from the blockbuster performance of some other oncology drugs.

The fierce clinical and commercial competition in the G12C space has already triggered a wave of retreats.

Novartis discontinued its Phase III KRAS G12C inhibitor JDQ443 in 2024, citing "increasing treatment options for patients with KRAS G12C-mutant cancers." Prior to this, Beta Pharma's KRAS G12C inhibitor BPI-421286 was also halted due to a lack of clear clinical advantages.

Verastem's exit is a rational and inevitable choice in this overcrowded field.

KRAS is one of the most common oncogenes, with mutations present in approximately 23%-25% of malignant tumors, affecting about 2.7 million new patients globally each year. Successfully targeting KRAS would open up a therapeutic market of immense potential.

According to DelveInsight's analysis, the total market size for KRAS inhibitors across seven major markets is projected to surge from $526 million in 2025 to $7.8 billion by 2034, with a compound annual growth rate of 35%. This positions it as one of the fastest-growing segments in the oncology treatment landscape.

No one wants to miss out on this vast opportunity. Verastem's choice is to abandon the increasingly saturated competition in KRAS G12C inhibitors and fully commit to the development of its KRAS G12D (ON/OFF) inhibitor, VS-7375.

John Hayslip noted that early data showed VS-7375 achieved a response rate (including both confirmed and unconfirmed responses) of 69% in treating 16 NSCLC patients with KRAS G12D mutations.

The drug was in-licensed by Verastem from GenFleet Therapeutics. In 2023, the two companies entered into a collaboration granting Verastem options for three pipeline assets outside Greater China. The deal included an upfront payment of $11.5 million and a potential total value of up to $625.5 million. Verastem designated VS-7375 as its lead program in December 2023 and exercised its option ahead of schedule in January 2025, securing development and commercialization rights for the drug outside Greater China.

The core advantage of VS-7375 lies in its "ON/OFF" dual-state inhibition mechanism.

The KRAS protein functions like a molecular switch, cycling between an inactive "OFF" state and an active "ON" state. Most approved and investigational KRAS inhibitors are allosteric inhibitors that can only bind and lock the protein in its "OFF" state—akin to installing an "off switch lock" on a malfunctioning switch, which has limited efficacy.

In contrast, as a dual-state inhibitor, VS-7375 can target both the "OFF" and "ON" states, directly blocking the active oncogenic signaling and achieving "round-the-clock" suppression of the KRAS pathway. This mechanism is considered by the scientific community to be a more promising, next-generation strategy with the potential to overcome drug resistance.

However, targeting G12D is far more challenging than targeting G12C. The KRAS G12C mutant contains a cysteine residue that can bind covalently to inhibitors, whereas KRAS G12D lacks this residue, making the development of effective inhibitors significantly more difficult.

This also explains why Bristol Myers Squibb (BMS), after acquiring Mirati Therapeutics and gaining its G12D inhibitor MRTX1133, ultimately abandoned the development of the program in March 2025 due to unstable pharmacokinetic data. MRTX1133 was a molecule developed based on the structure of Adagrasib, utilizing a pyrido[4,3-d]pyrimidine scaffold for screening and optimization.

Despite the significant challenges, the substantial unmet clinical need for G12D makes it a crucial battlefield. It is the most common subtype among all KRAS mutations, accounting for 27%. Among colorectal cancer and pancreatic cancer patients with KRAS G12 mutations, G12D represents as high as 44% and 46% of cases, respectively. Its potential market size may even surpass that of G12C.

In August 2025, Bayer entered into a global collaboration with Kumquat Biosciences for a G12D inhibitor, with a potential total value of up to $1.3 billion. In 2023, AstraZeneca secured the global exclusive license for YouSen Jianheng's G12D inhibitor UA022 with an upfront payment of $24 million and a potential total deal value of $395 million.

EvaluatePharma predicts that the global market for KRAS G12D-targeted therapies will reach $12 billion by 2035.

Currently, no KRAS G12D inhibitors have been approved globally, but the clinical race has intensified. According to Insight Database, there are 64 KRAS G12D inhibitors under development worldwide, with Chinese pharmaceutical companies contributing 39 of them. Companies like GenFleet Therapeutics, Allist Pharmaceuticals, Hengrui Medicine, and Qilu Pharmaceutical have all entered the fray.

In this race, the two most advanced candidates both come from China.

The first is GenFleet Therapeutics’ GFH375 (VS-7375), as mentioned earlier. In November 2025, GenFleet registered a Phase III clinical trial to evaluate the drug as a monotherapy compared to chemotherapy for treating metastatic pancreatic cancer, with progression-free survival and overall survival as primary endpoints.

Data presented at the 2025 ESMO Congress showed that among 59 evaluable pancreatic cancer patients, GFH375 achieved an objective response rate (ORR) of 41% and a disease control rate (DCR) as high as 97%. At a median follow-up of 141 days, 83% of patients had a progression-free survival (PFS) exceeding three months.

The other frontrunner is Hengrui Medicine’s HRS-4642. In October 2025, Hengrui initiated a Phase III study evaluating HRS-4642 in combination with chemotherapy as a first-line treatment for advanced pancreatic cancer, making it the first KRAS G12D inhibitor globally to enter Phase III clinical trials.

At the 2025 ESMO Congress, Hengrui also presented oral report results from a Phase Ib/II study of HRS-4642 in combination with gemcitabine and nab-paclitaxel (AG regimen) for treating advanced pancreatic cancer with KRAS G12D mutations.

After a median follow-up of 7.5 months, the data showed a confirmed ORR of 63.3%, with over half of the patients experiencing significant tumor shrinkage, a substantial improvement compared to standard chemotherapy. The DCR reached 93.3%, effectively controlling tumor growth in the majority of patients, whereas previous chemotherapy DCR typically did not exceed 70%.

Additionally, early data from Revolution Medicines’ zolondrasib (RMC-9805) showed an ORR of 61% and a DCR of 89% among 18 evaluable patients with KRAS G12D-mutated, previously treated non-small cell lung cancer.

Beyond targeting a single mutation, another mainstream approach involves incorporating the challenging G12D mutation into broader-spectrum "pan-KRAS" inhibitors.

With dozens of KRAS mutation subtypes, pan-KRAS inhibitors aim to target multiple mutations with a single drug. However, current pan-KRAS drugs do not cover all mutations but primarily focus on the most common high-frequency mutations, such as G12C, G12D, G12V, and G13D.

Currently, there are nearly 35 pan-KRAS inhibitors under development globally, primarily following two technological pathways.

One is the molecular glue approach, represented by Revolution Medicines’ RMC-6236, which is currently the most advanced pan-KRAS pipeline and has entered Phase III clinical trials.

The other pathway is small molecule inhibitors, chosen by companies such as Eli Lilly, Pfizer, and BeiGene.

In December 2025, Jacobio Pharmaceuticals’ oral small molecule pan-KRAS inhibitor JAB-23E73 was licensed to AstraZeneca in a deal with a potential total value exceeding $2 billion, marking a landmark business development case in the pan-KRAS field in recent years.

JAB-23E73 does not rely on interactions with the 12th amino acid of KRAS but instead interacts with other regions of KRAS, making it effective against various KRAS mutations. Compared to the molecular glue approach, which is associated with higher incidences of rash and mucositis, small molecule pan-KRAS inhibitors have demonstrated significantly optimized safety profiles in early clinical trials, particularly with markedly reduced incidences of skin and oral-related toxicities. This provides a critical advantage for patients to receive sustained, full-dose treatment while maintaining their quality of life.

The battle for KRAS is far from over; it has merely shifted its direction of attack.

As the G12C landscape gradually becomes clear, the battles for G12D and pan-KRAS are just beginning to intensify. The core of the competition is quietly shifting. The true determinant of victory lies not in who arrives first but in whose chosen path can establish a new benchmark for the next generation of therapies, thereby dominating the rules of the game for the next decade.